Previous studies in both the conscious dog and isolated dog lung indicate that inhibiting the synthesis of cyclooxygenase products of arachidonic acid (AA) metabolism increases pulmonary vascular tone or resistance (PVR). Which pathways or products of AA metabolism (i.e. eicosanoids) account for this pulmonary hypertension is not clear. The proposed investigation, conducted in the isolated canine lung lobe blood-perfused at constant flow, will determine whether the increase in PVR associated with cyclooxygenase inhibition (COI) is related to a diminished formation of vasodilator prostaglandins (i.e. prostacyclin) or diversion of AA metabolism toward the formation of vasoconstrictor lipoxygenase products (i.e. leukotrienes) or involves other endogenous vasoactive substances (histamine, norepinephrine or serotonin). The proposed studies will correlate circulating levels of various eicosanoids with changes in PVR and the segmental distribution of PVR attendant to varying degrees of COI induced by three chemically dissimilar cyclooxygenase inhibitors (aspirin, meclofenamate and indomethacin). Studies from our laboratories also suggest that vasoactive amines like serotonin (5-HT) trigger the synthesis of AA metabolites by the lung which in turn act to modulate the vasopressor response to 5- HT. The proposed studies will determine which pathways and/or products of AA metabolism affect the pressor response to 5-HT in the lung by measuring various AA metabolites in the blood and by employing specific antagonists of AA metabolism (prostacyclin synthetase inhibitors, 15-HETE and tranycypromide sulfate; lipoxygenase inhibitors, nordihyroguairetic acid and caffiec acid). Studies in peripheral vascular beds suggest that some vasoactive amines may trigger both smooth muscle contraction and AA metabolism by changes in calcium (Ca++ conductance via functionally distinct Ca++ channels. The proposed studies will determine whether 5-HT evokes pulmonary smooth muscle contraction by promoting Ca++ mobilization via voltage operated channel (VOC) or receptor-operated channels (ROC) by employing Ca++ channel antagonist specific for either a VOC (verapamil, diltiazem, nitrendipine) or ROC (nitroprusside, nitroglycerin) and VOC patentiators (BAY K 8644). The effect of Ca++ channel antagonists upon AA metabolism and the hypertension associated with COI will also be examined. The proposed investigations will provide new insights into the mechanism and physiological significance of interactions between serotonin and metabolites of AA in the regulation of pulmonary vasoreactivity.